The overall goal is to identify genes that modify the age-at-onset of Alzheimer's disease (AD). There are four known AD loci: 1) the amyloid precursor protein (APP) gene on chromosome 21;2) the PSEN1 gene on chromosome 13;3) the PSEN2 gene on chromosome 1;4) the chromsome 19 apolipoprotein (APOE) gene. Mutations in APP and PSEN1 exhibit autosomal dominant inheritance of AD. Penetrance of disease is age-dependent and complete by 65 years (early-onset AD). PSEN2 mutations are also inherited by an autosomal dominant mechanism, but penetrance is extended over a much longer age-span. In PSEN2 carriers, AD onset ranges from 43 to >89 years. APOE is a susceptibility gene for AD. Inheritance of the APOE epsilon4 allele increases the risk of developing AD, but this allele is neither necessary nor sufficient to cause AD. The epsilon4 allele modifies the onset-age of PSEN1- and PSEN2-induced AD. Numerous other candidate regions and genes have also been suggested, though none has been unambiguously confirmed. The general hypotheses are: 1) The onset age of PSEN1- and PSEN2-induced AD is variable and determined at least in part by other inherited modifier loci. These modifier genes include APOE and other as yet unidentified loci;2) The location of these modifier genes can be identified by linkage analysis of PSEN1 and PSEN2 AD families. The actual genes responsible for onset modification can be identified by positional cloning methods. We will perform linkage analysis of PSEN1 and PSEN2 families using APOE as a covariant, and age-of-onset as a quantitative trait. Markov chain Monte Carlo analysis methods will be used to detect modifier loci. The families to be studied include the Volga German families (PSEN2N141-1 mutation), a large Columbian family (PSEN1 E280A mutation), and a group of PSEN1 mutation families assembled by the University of Washington Alzheimer's Disease Research Center. In addition, APOE haplotypes constructed from a panel of 21 single nucleotide polymorphism sites will be examined to determine APOE sites other than the epsilon2/epsilon3/epsilon4 polymorphisms contribute to the modification of the age of AD onset.